It is planned to investigate the HLA associations of 6 selected disease states (Alzheimer's disease, systemic lupus, myasthenia gravis, insulin-dependent diabetes, multiple sclerosis, and rheumatoid arthritis) in order to test 4 hypotheses about HLA and disease: (1) that the association may in some instances be mainly with the public antigen or cross-reactive groups, (2) certain diseases may reflect association with a subdeterminant on more than one private specificity, (3) the association may be with variants of the private specificity, (4) the association may be antigenic systems linked to HLA but not yet defined. The first 3 hypotheses stem from the proposition that HLA antigens contain framework, cross-reacting, and 2 or more categories of polymorphic determinants. The latter would include one determinant, or a group of subdeterminants, which therefore might be shared by more than one specificity (like the Rh system). To carry out this work, we will augment our large existing library of HLA typing sera by developing a library of monoclonal antibidies using mouse hybridomas, and will seek to develop human-human hybridomas for monoclonal anti-HLA antibodies. The diseases will also be considered from the standpoints of their possible clinical subdivisions, with special emphasis on Alzheimer's disease.